Roughly 500,000 cancer patients are treated with radiotherapy each year. Acute and late sequelae of radiotherapy have a negative impact upon the quality of life of cancer survivors. These sequelae include proctitis, cystitis, esophageal stricture, cutaneous fibrosis plus others. We propose a novel means of preventing the acute and late radiation injury to normal tissues in these patients. Inhibitors of GSK-32 pathway can serve as radiation protective agents. Lithium can inhibit the GSK-32 pathway. Lithium-containing topical formulations are candidates for being effective radioprotectors by delivering the metal ion to the basal cell layer of epidermis (progenitor cells), preventing radio-induced apoptosis in normal cells in the skin overlying areas of radiation treatment. A total 12 prototype formulations will be screened in a radiation-induced injury porcine model. Six of the formulations will contain lithium succinate and the other six will contain lithium lactate. Two levels of the lithium salts will be screened (1% and 10%), each as an ointment, a gel, and an emulsion (cream). The best formulation(s) will be selected based on induction of proteins that enhance cell viability and inhibition of radiation-induced apoptosis. The efficacy and safety of selected formulations will be optimized in Phase II, supporting proof-of-concept for testing in humans and an IND submission to the FDA. PUBLIC HEALTH RELEVANCE: Over 500,000 cancer patients are treated with radiotherapy each year, and there are presently 10,000,000 cancer survivors in the US. Acute and late sequelae of radiotherapy have a negative impact upon the quality of life of cancer survivors. The goal of this proposal is to attenuate skin injury through development of a topical drug that markedly enhances the viability of the epidermis when administered before irradiation therapy to cancer patients undergoing targeted treatment of deeper tumors with radiation therapy.